(1) Field of the invention
This invention relates to a dipeptide, tyrosyl-arginine, comprised of the amino acids tyrosine and arginine and the use of this dipeptide as a nutrient supplement to intravenous nutrition.
(2) Description of Related Art
Intravenous nutrition has become an important therapy for patients who are unable to adequately nourish themselves by oral nutrition. While current methods of intravenous nutrition allow the maintenance of good health for prolonged periods there are continuing complication with the method of administration, and the problem of poor utilization of intravenous nutrition, compared with oral nutrition, has yet to be solved. There is mounting evidence that the amino acid solutions that are available on the market do not provide the most efficient balance of "essential" and "non-essential" amino acids. Possibly the major problem in assessing the correct balance is establishing which amino acids are indispensable and determining the particular amino acid requirements of specific populations.
In a series of experiments in the 1940's and 1950's Rose et al., Nutr. Abstr. Rev. 27, 6731-647, defined a group of eight amino acids which were considered to be essential or indispensable for normal adult health. These amino acids--isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine--have since been shown in similar studies to be indispensable for women, children and infants (for a recent review see Laidlaw S. A. and Kopple, J. D. (1987) Am J. Clin Nutr 46, 593-605). It was tacitly assumed that the other amino acids were nonessential, and thus could be synthesized de novo from the eight essential amino acids.
In recent years with the improved techniques of amino acid analysis, and the development of chemically defined diets for parenteral and enteral nutrition the dispensibility of a number of classically considered nonessential amino acids has been questioned.
Tyrosine, for example, is considered to be a nonessential amino acid since under normal conditions it can be synthesized readily from phenylalanine via the phenylalanine hydroxylase reaction. This is the only pathway for de novo synthesis of tyrosine, and its inclusion in the diet exerts a sparing effect on the dietary phenylalanine requirement. Thus, when there is a deficiency in phenylalanine hydroxylase, as in classic phenylketonuria, an absolute requirement for tyrosine is expected.
There is now very good evidence to suggest that tyrosine is also indispensable for infants, and malnourished patients with alcoholic cirrhosis. Infants maintained on diets devoid of tyrosine showed decreased plasma tyrosine levels, impaired nitrogen retention and impaired weight gain, Snyderman S. E. (1971) Metabolic Processes in the F.ang.etus and Newborn Infant (Ionxix JHP, Visser HKA, Troelstra JD, eds.), pp. 128-141, Leiden: HE Stenfert Kroesse NV. The reintroduction of tyrosine to the infants diet normalized plasma tyrosine levels, and improved nitrogen retention and weight gain. Similarly, malnourished cirrhotic patients maintained on a standard parenteral nutrition solution (devoid of tyrosine) exhibited depressed tyrosine, cystine and taurine levels, markedly elevated phenylalanine and methionine levels, and remained in neutral or negative nitrogen balance, Rudman, D., Kutner, M. Ansley, J. et al. (1981) Gastroenterology 81, 1025-1035. When these patients were given an oral supplement containing tyrosine and cystine, nitrogen balance became strongly positive, plasma phenylalanine and methionine levels dropped, and plasma taurine, tyrosine and cystine levels rose to normal levels. It has been postulated that as for classic phenylketonuria infants and malnourished patients with cirrhosis have a hepatic deficiency in phenylalanine hydroxylase, Laidlaw SA and Kopple JD (1987) Am J Clin Nutr 46, 593-605.
Finally, there is suggestion that tyrosine may be required by patients undergoing intravenous nutrition therapy. It has been observed that in a group of nonstressed patients receiving 0.3 gN/kg/day of a commercially available intravenous solution, an amount well in excess of recommended daily requirements, that plasma levels of tyrosine, cysteine and glutamate remained in low fasting range while phenylalanine, leucine and isoleucine were increased to postprandial levels, Loder PB, Smith RC, Kee AJ, et al. (1990) Ann Surg (In Press). The rise in phenylalanine in relation to tyrosine may indicate inefficient conversion of phenylalanine to tyrosine in these non-stressed patients.
Based on this evidence there appears to be an absolute requirement for tyrosine (and cystine) in states of metabolic disorder, immaturity, or in severe stress. Furthermore, patients receiving intravenous nutrition may require more tyrosine and cystine than is available in current formulations.
Commercial intravenous nutrition solutions contain only a small amount of tyrosine & cysteine. This is because tyrosine and cysteine have limited solubility and the provision of even small amounts is difficult without the risk of precipitation. Additionally, some amino acids such as glutamine and asparagine are heat labile while others like cysteine, cystine and methionine are prone to oxidation.
A novel method of providing these otherwise difficult amino acids has been proposed through the use of dipeptides, Adibi SA (1987) Metabolism 36, 1001-1011. This suggestion has gained considerable attention as dipeptides have a number of additional advantages. Such advantages include (i) the ability to meet the nitrogen requirements of patients with severe fluid restriction such as the critically ill and renal failure patients and (ii) the reduction in hypertionicity of intravenous nutrition solutions by the substitution of amino acids with dipeptides permitting the possibility of intravenous nutrition delivery via a peripheral vein. Peripheral intravenous nutrition would avoid the hazards of central venous catheterization and reduce the complications of hypertonic solutions.
The initial investigations into the use of dipeptides as an amino acid and nitrogen source in intravenous nutrition commenced in the early 1970's. Since then extensive work performed on animal models have demonstrated the mechanisms of dipeptide clearance, the metabolism of the constituent amino acid residues, peptide utilization under conditions of constant infusion, peptide utilization under conditions of total parenteral nutrition, the influence of peptide structure on peptide metabolism, the potential of dipeptides as a sole nitrogen source in total parenteral nutrition, and the long term efficacy and safety of dipeptide mixtures, (Adibi SA (1987) Metabolism 36, 1001-1011 and Furst P, Albers S, Stehle P (1987) Contr Infusion Ther Clin Nutr 17, 117-136.
Clinical trials in man have just commenced and preliminary results support the conclusions drawn from animal models that dipeptides are a safe and efficacious alternative substrate for parenteral nutrition, Adibi SA (1989) Metabolism 38 (Suppl. 1), 89-92, Albers S. Wernerman, J. Stehle, P. et al. (1988) Clin. Sci. 75, 463-468, Alberts, S., Wernerman, J., Stehle, P., et al. (1989) Clin. Sci. 76, 643-648, Brandl M, Sailer, D., Langer, K., et al. (1987) Contr Infusion Ther. Clin. Nutr. 17, 103-116, Hubl, W., Druml, W., Langer, K., et al. (1989) Metabolism 38 (Suppl. 1), 59-62, Stehle, P., Zander, J., Mertes, N., et al. (1989) Lancet 1, 231-233 and Steininger, R., Karner, J., Roth, E., et al. (1989) Metabolism 38 (Suppl. 1), 78-81.
To date the peptides which have received most attention are glycl- and alanyl-dipeptides, Adibi SA (1987) Metabolism 36, 1001-1011, Adibi SA (1989) Metabolism 38 (suppl 1), 89-92, Furst, P., Albers, S., Stehle, P. (1987) Contr Infusion Ther Clin Nutr 17, 117-136. These dipeptides are thought by many, Adibi SA (1987) Metabolism 36, 1001-1011, to be more suitable for intravenous nutrition than other dipeptides with alternate N-terminal amino acid residues as they exhibit a more prolonged plasma half-life, and, thus a greater proportion of the infused dipeptides would reach the tissues intact. The rationale that dipeptides must reach the tissues intact for efficient utilization we believe to be unfounded. It is well know that intravenously administered free amino acid solutions are taken up and are utilized efficiently by the tissues of the body. In fact, this is the normal physiological situation; any peptides taken up by the intestinal mucosa and released into the portal blood stream are hydrolysed to their constituent amino acids before reaching the systemic circulation. Thus rapid hydrolysis of peptides in the blood stream should not hamper but should enhance utilization of amino acids by the tissues.
Furthermore, the infusion of peptide mixtures entirely based on glycyl- and alanyl-dipeptides may not be within the framework of physiological nutrition nor be applicable in clinical practice.
In this regard it must be remembered that glycine infused in excess is an inferior source of nitrogen, Jurgens, P., and Dolif, D. (1972) Parenteral nutrition (Wilkinson, ed.), pp. 77-92, Churchill Livingstone, London, and it is also questionable whether cells are able to cope with large intravenous loads of individual amino acids. Based on the problems associated with the above discussed peptides, an alternate method to deliver tyrosine and cystine than the n-terminal glycine or alanine carrier.